Cancer in adolescents and Young Adults

17 th ESO-ESMO Masterclass in Clinical Oncology 24-29 March 2018, Cancer in adolescents and Young Adults Laurence Brugières Gustave Roussy Cancer Center Villejuif, France

Cancer in TYA A rare disease in patients in transition between childhood and adulthood 15-19 y 15-25 y 15-39 y 2

Medical challenges in AYA A unique spectrum of rare cancer types Long time to referral Multiple therapeutic options : need for a double expertise: site and age specific Distinct tumor biology in this age group Low rate of inclusion into trials Specific psycho-social needs Fertility preservation and long term follow-up

Epidemiology Estimated TYA (15-24 y) population in European Union: 58 million 14 000 new cancer cases/year In TYA in Europe Cancer is the second cause of death in TYA 4

A unique spectrum of cancer types 120 100 80 60 40 20 0 15-19 ans 20-24 ans Miscellaneous Carcinoma Germ cell tumor Soft tissue sarcoma Bone tumor Brain tumortumeurs cérébrales Lymphoma Leucémies

A unique spectrum of cancer types N. Gaspar Need for collaboration Children TYA Adults Age (y) 6

N. Gaspar Lymphomas Hodgkin LNH

N. Gaspar Bone tumors Osteosarcoma Ewing Chondrosarcoma

N. Gaspar Soft tissue sarcomas RMS Non RMS sarcomas

N. Gaspar Gonadal tumors

N. Gaspar Brain tumors

N. Gaspar Carcinomas Breast Colon Thyroid Genetic predisposition syndromes

Melanomas Prevention N. Gaspar Trunk

Medical challenges in AYA A unique spectrum of rare cancer types requering expertise Long time to referral Multiple therapeutic options : need for a double expertise: site and age specific Distinct tumor biology in this age group Low rate of inclusion into trials Specific psycho-social needs Fertility preservation and long term follow-up

Late referral Aspecific symptoms Insuffisant awareness that cancer may happen in this age group Diagnostic pathway often complex with multiple consultations and consequent delay Median delay for diagnosis : 8 weeks for TYA and weeks in young adults in France N. Gaspar Pain Fatigue Weight loss Fever Sueurs lump Delay shorter in patients < 12 y Étude EXECADO, E desandes France 2006-2007

Delays in diagnosis and treatment in French TYA Desandes in press 2018 27/03/2018 Dr N.Gaspar 16

Timely referral

Survival Improvement Gap in 5-year relative survival 1975-1997 (invasive cancer) Survival Improvement Gap: Improvement in 5-Year Relative Survival, Invasive Cancer, 1975 1997 From SEER data

Survival (316699 cancer diagnosed in E Europe in patients <39 y) 5-y OS 76% (95% CI 75 77) in children 5-year relative survival estimates by age at diagnosis and by sex, for all cancers combined, diagnosed in Europe in 2000 07 Trama 2016 Lancet Oncol 5-y OS 79% (78.9 79 3) in TYA 20

Cancer in TYA in Europe 2000-2007 5-y survival Trama 2016 Lancet Oncol 21

Trends in 5-year OS in 5 cancer categories 1999-2007 22

ALL : outcome better with pediatric protocols N. Gaspar Orenalla Lona, 2018 Current Hematologic Malignancy Reports

ALL in teengagers : outcome according to the site of treatment 1,8,6,4,2 0 N. Gaspar p=.005 82% 56% 0 1 2 3 4 5 6 7 8 9 Temps (années) Pédiatrie ------ Adulte 1,8,6,4,2 0 p=.004 CHIMIO!!! Pédiatre 83% 67% Pédiatrie ------ Adulte 0 1 2 3 4 5 6 7 8 9 Temps (années)

Hodgkin lymphoma : cost of cure 25

Frequency of recurrent cytogenetic abnormalities in B-ALL with age Tricoli, Cancer 2016 27

Children AJA????? Adults Molecular biology C+ C- CINSARC GI Meta Complexity Index in Sarcoma C+ C- N. Gaspar Courtoisie de F. Chibon GI+ GI- Genomic Index prognostic signatures GI+ GI- M+ M- M+ M-

N. Gaspar Molecular profile according to age Médulloblastoma Kool et al. Cancer cell 2014

N. Gaspar Need to increase tumor banking

Low inclusion rates in clinical trials 51,395 patient inclusions in US National cooperative group trials 1997-2003 Also reported in Australia Canada Italy UK France Ferrari and Bleyer, 2007

TYA Inclusion rate higher in diseases where JOINT paediatric/adult trials are available Highest rate of teenage accrural But still not sufficient in young adults Fern et al. TLO 2014

Low rate of inclusion in clinical trials Only few common trials for adult and children with the same tumor types The best are bone tumors Age limit of inclusion in most clinical trials : 18 y «No diseases begin or end at age 18 years» Sallan, Hematology 2006 N. Gaspar 34

Brentuximab vedotin Delay of drug access in common diseases e.g. Hodgkin disease Adult Phase I trial 18 years Relapsed or refractory CD30 positive HL NCT00430846 Published Nov 2011 Nivolumab, 2012-15 Approved for adult relapsed or refractory HL (2012) Successful trial of BV + Chemotherapy in Adults Stage II-IV HIV- HL, first line TT NCT01771107 March 2013-2017 TYA disease Approved by FDA for front line tt of high risk HL 2018 April 2012 2018 Paediatric Phase-I/II trial of BV < 18 years for R/R HL NCT01492088 Randomized Phase 3 Study of BV for Newly Diagnosed High- Risk HL in Children and Young Adults (<21 y)

N How to improve acess to new drugs? FAIR Trials working group: Proposal https://doi.org/10.1093/annonc/mdy002 36

Unique complex psycho-social needs Many challenges - Loss of control and independence - Self-image dissatisfaction - Difficulty establishing relationships, - Sexuality self-confidence - Limitation of «normal» activities. Need for a specific environment providing - respects AYA privacy and dignit - peer-group support, - psychologists, - education and vocational mentors, - specialists nurses, - social workers, - activity coordinators Communication skills required to improve compliance and treatment adherence; Adopt a familycentred approach Several models : - TYA units - Dedicated teams in adult and pediatric centers 38

Compliance : Non compliance is a major issue in adolescent oncology Crucial problem with orally administered anticancer therapy Prevention : o Fair and complete information o Good interaction between the adolescents and health providers o Early recognition at the time of diagnosis those patients at risk of non-compliance so that preventive measures can be instituted N. Gaspar 39

Specific needs of AYA Professional team trained to interact with AYA familiar with communication issues specific to the emotional fragility of this age group able to give them a clear, appropriate and comprehensive information at all stages and a level of control on the decision making system Environment designed for young people with age appropriate facilities The possibility to keep the social life as normal as possible ~ trying to keep links with family members and their peers Contact with peers experiencing the same problems Facilitation of education

Excess of morbidity and mortality Excess of morbidity 15-29 y, 1975-2005 Robison, Nature review cancer, 2014 Excess of mortality 15-39 y, 1975-2000 At 5 y HR 1.76 At 20 y HR 1.36 Youn, Cancer, 2014 42

Long term side effects in survivors Less cardiotoxicity of anthracyclines in adolescents/children Less ototoxicity of cisplatinum in ado vs children Relative risk of deafness in 74 osteosarcoma Mulrooney et al. BMJ. 2009, Dec 8; 339 Stöhr et al. Cancer Investigation, 23:201 207, 2005 Lewis et al. Pediatr Blood Cancer 2009;52:387 391

Main long term side effects in survivors after a cancer in TYA 9 8 7 6 5 4 3 2 1 0 Hazard Ratio Population < 25ans 1981-2003 59% 24% 7.5% 7.8% 6.8% Brewster, BJC, 2014

Fertility preservation : a prerequisite before beginning cancer treatment in TYA INFORMATION about fertility issues in all cases SPERM BANKING in men FERTILITY PRESERVATION before or after treatment in females according to risk 45

Long term follow-up Systematic plan for screening, surveillance, and prevention Adapted to the risks associated to previous cancer, cancer therapy, genetic predispositions identified or suspected, lifestyle behaviors, Comorbidities Life-long in high risk patients 46

National and international collaborations for TYA oncology European Network for Teenagers and Young Adults with Cancer EMSOS- SIOPE group Several national groups for TYA oncology 47

Several models of care TYA units allowing to have - a multiprofessional team trained to TYA oncology - Involvement of both pediatric and adult oncologists in the same structure - Access to all clinical trials available for this age group - Environment adapted to this group of patients - Pairs groups Organ centered care - patients are treated by organ specialists - with the help of a multi-disciplinary teams dedicated to provoded age appropriate TYA support

Cancers in TYA More than 75% of TYA with cancer will survive. The quality of care (including choice of 1st line treatment, environment, psycho-social support, long term follow-up) of major importance to improve their quality of life after cancer treatment For those patients with high risk cancer collaborations between all groups to foster research and access to new drugs Is crucial

Thanks